Treatment of lean PCOS teenagers: a follow-up comparison between Myo-Inositol and oral contraceptives.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder widely diffused and diagnosed in women of reproductive age. The pathology exhibits alteration of the reproductive functions, including conditions as hyperandrogenism, menstrual cycle irregularity, type 2 diabetes. These conditions are visible in the patients through phenotypical manifestations as hirsutism, acne, and obesity. Even if the syndrome is characterized by common features among both adult and adolescent women, the diagnostic criteria are different for the two age categories and to date still controversial. We investigated different treatments in PCOS adolescents with non-severe metabolic conditions, to evaluate which could be the appropriate therapeutical approach for these patients. PATIENTS AND METHODS: We enrolled lean teenagers with PCOS, and we divided the patients in two age ranges: 13-16 years old and 17-19 years old. They were treated for 3 months either with oral contraceptive pills (OCP) drospirenone/ethinylestradiol (group A), myo-Inositol (myo-Ins) (group B), or OCP plus myo-Ins (group C). Data were analyzed with a descriptive statistics summarizing quantitative variables including median, 25th and 75th percentiles. RESULTS: We pointed out that the group of 13-16 years old lean teenagers treated with myo-Ins exhibit a significant decrease of weight and body mass index (BMI), and an effective improvement the metabolic and hormonal parameters achieved with a non-pharmacological treatment. In the older teenagers aged 17-19 years, data highlights that myo-Ins treatment in combination with OCP prevents the increases of weight and BMI, improves the metabolic profile of the patients, and strongly ameliorates the hormonal parameters analyzed. CONCLUSIONS: The results indicate a different scenario in the two age ranges considered and interestingly suggest an important role of myo-Ins in the PCOS context. A therapy based on this natural compound alone or in combination with OCP seems effective to improve both metabolic and hormonal parameters of PCOS adolescents and thus could represent a novel and valid option to consider for the treatment of this syndrome.

Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer.

PURPOSE: In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response. EXPERIMENTAL DESIGN: We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression. RESULTS: Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (P < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, P = 0.0018; 20 vs. 52 weeks, P = 0.0003; 14 vs. 40 weeks, P = 0.0001; 20 vs. 56 weeks, P = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, P = 0.02). CONCLUSIONS: Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non-AR-directed therapy.

Overall and bleeding-related discontinuation rates of a new oral contraceptive containing 4 mg drospirenone only in a 24/4 regimen and comparison to 0.075 mg desogestrel.

OBJECTIVES: Progestin-only pills do not increase the risk of venous thromboembolism, stroke, and myocardial infarction but are associated with poor cycle control. A novel estrogen-free pill containing only drospirenone (DRSP) to improve bleeding patterns and tolerability and reduce discontinuation rates has been introduced into the market. The present study aims to describe the improvement in the acceptability of this DRSP-only pill, e.g. regarding the bleeding profile and the reduction in discontinuation rates due to unacceptable bleeding compared to desogestrel (DSG). STUDY DESIGN: Double-blind, double-dummy prospective phase III study in healthy women aged 18-45 years evaluating a total of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles. RESULTS: Overall, 82 (9.6%) women in the DRSP group and 44 (13.3%) women in the DSG group experienced treatment-emergent adverse events (TEAEs) leading to premature termination of the trial meaning that 32% more women in the DRSP group finished the trial in comparison to the DSG group (based on the AUC of Kaplan-Meier's curves). Discontinuation rates due to abnormal bleeding were 3.7% for DRSP and 7.3% for DSG users. This is a 55.7% lower discontinuation rate in the DRSP group compared to the DSG group. CONCLUSIONS: This report describes the improvement in acceptability and bleeding profile of women using the new DRSP-only oral contraceptive compared to DSG, providing a better quality of life and adherence to the contraceptive method as demonstrated by lower discontinuation rates of women using the estrogen-free DRSP-only pill.

Population Pharmacokinetics of Ipatasertib and Its Metabolite in Cancer Patients.

Ipatasertib is a selective AKT kinase inhibitor currently in development for the treatment of several solid tumors, including breast and prostate cancers. This study was undertaken to characterize pharmacokinetic profiles of ipatasertib and its metabolite M1 (G-037720) and to understand the sources of variability. Population pharmacokinetic models of ipatasertib and M1 were developed separately using data from 342 individuals with cancer from 5 phase 1 and 2 studies. The final population pharmacokinetic models for ipatasertib and M1 were 3-compartmental, with first-order elimination and sequential zero- and first-order absorption. Ipatasertib bioavailability and M1 formation increased after multiple dosing, resulting in an increase in exposure beyond that expected from accumulation alone. Covariate effects of ipatasertib include decreased oral clearance with increasing age and with coadministration of abiraterone, as well as decreased bioavailability with increasing weight. For ages 37 and 80 years, steady-state area under the curve (AUCss ) was predicted to be 81% and 109%, respectively, of the typical population value (64 years). For body weight of 49 and 111 kg, AUCss was predicted to be 132% and 78%, respectively, of the typical population value (75 kg). The small magnitude of change in ipatasertib exposure is not likely to be clinically relevant. For M1, the peripheral distribution volume and intercompartmental clearance increased with increasing weight. Coadministration of abiraterone was estimated to increase M1 exposure by 61% at steady state. Mild and moderate renal impairment, mild hepatic impairment, and race were not identified as significant covariates in the final models for ipatasertib and M1.

Association of Chemotherapy, Enzalutamide, Abiraterone, and Radium 223 With Cognitive Function in Older Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Older adults are at greater risk of cognitive decline with various oncologic therapies. Some commonly used therapies for advanced prostate cancer, such as enzalutamide, have been linked to cognitive impairment, but published data are scarce, come from single-group studies, or focus on self-reported cognition. Objective: To longitudinally examine the association between cognitive function and docetaxel (chemotherapy), abiraterone, enzalutamide, and radium Ra 223 dichloride (radium 223) in older men with metastatic castration-resistant prostate cancer. Design, Setting, and Participants: A multicenter, prospective, observational cohort study was conducted across 4 academic cancer centers in Ontario, Canada. A consecutive sample of 155 men age 65 years or older with metastatic castration-resistant prostate cancer starting any treatment with docetaxel, abiraterone acetate, enzalutamide, or radium Ra 223 dichloride (radium 223) were enrolled between July 1, 2015, and December 31, 2019. Exposures: First-line chemotherapy (docetaxel), abiraterone, enzalutamide, or radium 223. Main Outcomes and Measures: Cognitive function was measured at baseline and end of treatment using the Montreal Cognitive Assessment, the Trail Making Test part A, and the Trail Making Test part B to assess global cognition, attention, and executive function, respectively. Absolute changes in scores over time were analyzed using univariate and multivariable linear regression, and the percentages of individuals with a decline of 1.5 SDs in each domain were calculated. Results: A total of 155 men starting treatment with docetaxel (n = 51) (mean [SD] age, 73.5 [6.2] years; 34 [66.7%] with some postsecondary education), abiraterone (n = 29) (mean [SD] age, 76.2 [7.2] years; 18 [62.1%] with some postsecondary education), enzalutamide (n = 54) (mean [SD] age, 75.7 [7.4] years; 33 [61.1%] with some postsecondary education), and radium 223 (n = 21) (mean [SD] age, 76.4 [7.2] years; 17 [81.0%] with some postsecondary education) were included. Most patients had stable cognition or slight improvements during treatment. A cognitive decline of 1.5 SDs or more was observed in 0% to 6.5% of patients on each measure of cognitive function (eg, 3 of 46 patients [6.5%; 95% CI, 2.2%-17.5%] in the group receiving chemotherapy [docetaxel] had a decline of 1.5 SDs for Trails A and Trails B). Although patients taking enzalutamide had numerically larger declines than those taking abiraterone, differences were small and clinically unimportant. Conclusions and Relevance: These findings suggest that most older men do not experience significant cognitive decline in attention, executive function, and global cognition while undergoing treatment for advanced prostate cancer regardless of the treatment used.

Addition of docetaxel or abiraterone to androgen deprivation therapy in metastatic hormone-sensitive prostate cancer in Indian population.

BACKGROUND: The addition of docetaxel or abiraterone to androgen deprivation therapy (ADT) achieves superior survival outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) in predominantly Western population. We sought to evaluate the treatment outcomes of adding docetaxel or abiraterone to ADT in Indian population. METHODS: We reviewed the medical records of ninety patients with newly diagnosed mHSPC who received treatment between January 2015 and June 2018. Patients received ADT alone or ADT + docetaxel or ADT + abiraterone as initial treatment. Monthly clinical evaluation and prostate-specific antigen (PSA) measurement were done. Outcome measures analyzed included PSA decline <90%, serological complete response (sCR) (PSA < 0.2 ng/ml), and progression to CRPC. Outcome variable was compared using Fisher's exact test. RESULTS: Patients received ADT alone (n = 37) or ADT + docetaxel (n = 31) or ADT + abiraterone (n = 22). The median age was 67.5 years (range, 41-87 years) and the median PSA was 88.5 ng/ml (range, 1.12-4000). PSA decline <90% was seen in 22 (73%), 24 (86%), and 17 (94%) patients in the ADT alone, ADT + docetaxel, and ADT + abiraterone groups. sCR was achieved in 5 (17%), 10 (36%), and 9 (50%) patients in the ADT alone, ADT + docetaxel, and ADT + abiraterone groups. Progression to CRPC was observed in 18 (60%), 11 (39%), and 2 (11%) patients in the ADT alone, ADT + docetaxel, and ADT + abiraterone groups. CONCLUSION: The addition of docetaxel or abiraterone to ADT achieves a deeper serological response and reduces progression to CRPC compared to ADT alone in mHSPC patients of Indian origin. Longer follow-up is required to comment on overall survival and also to determine which combination (ADT + docetaxel or ADT + abiraterone) is superior to others, if at all.

Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population. OBJECTIVE: To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC. DESIGN, SETTING AND PARTICIPANTS: A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using Χ2. RESULTS AND LIMITATIONS: One hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P < 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P > 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively). CONCLUSIONS: Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.

Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p.

Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3'-untranslated region (3'UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR-579-3p indeed binds to the SLCO1B3 3'UTR and significantly inhibited SLCO1B3 reporter activity. Treatment with abiraterone significantly downregulated hsa-miR-579-3p, indicating its potential role in upregulating SLCO1B3 expression. In this study, we demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression, a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics.

Stereotactic body radiotherapy for oligoprogressive lesions in metastatic castration-resistant prostate cancer patients during abiraterone/enzalutamide treatment.

BACKGROUND: Metastasis-directed therapy (MDT) utilizing stereotactic body radiotherapy (SBRT) for oligoprogressive lesions could provide a delay in next-line systemic treatment (NEST) change while undergoing androgen receptor-targeted agents (ARTA) treatment. We evaluated prognostic factors for prostate cancer-specific survival (PCSS) and progression-free survival (PFS) to characterize patients receiving treatment with ARTA who may benefit from MDT for oligoprogressive lesions. The impact of MDT on delaying NEST and the predictive factors for NEST-free survival (NEST-FS) were also assessed. MATERIALS AND METHODS: The clinical data of 54 metastatic castration-resistant prostate cancer patients with 126 oligoprogressive lesions receiving abiraterone (1 g/day) or enzalutamide (160 mg/day) before or after systemic chemotherapy were analyzed. A median of three lesions (range: 1-5) were treated with MDT. The primary endpoints were PCSS and PFS. The secondary endpoints were time to switch to NEST and NEST-FS. RESULTS: The median follow-up time was 19.1 months. Univariate analysis showed that the number of oligoprogressive lesions treated with SBRT and the time between the start of ARTA treatment and oligoprogression were significant prognostic factors for PCSS, and the timing of ARTA treatment (before or after chemotherapy) and the prostate-specific antigen (PSA) response after MDT were significant prognostic factors for PFS. Multivariate analysis showed that early MDT for oligoprogressive lesions delivered less than 6 months after the beginning of ARTA and higher PSA levels after MDT were significant predictors of worse PCSS and PFS. The median total duration of ARTA treatment was 13.8 months. The median time between the start of ARTA treatment and the start of MDT for oligoprogressive lesions was 5.2 months, and MDT extended the ARTA treatment by 8.6 months on average. Thirty-two (59.3%) patients continued ARTA treatment after MDT. ARTA treatment after chemotherapy, early oligoprogression requiring MDT, and lower radiation doses for MDT were independent predictors of NEST-FS in multivariate analysis. CONCLUSIONS: MDT for oligoprogressive lesions is effective and may provide several benefits compared to switching from ARTA treatment to NEST. Patients with early progression while on ARTAs and inadequate PSA responses after MDT have a greater risk of rapid disease progression and poor survival, which necessitates intensified treatment.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer.

Men with circulating tumor cell (CTC) AR-V7-positive metastatic castration-resistant prostate cancer (mCRPC) have worse outcomes when treated with enzalutamide/abiraterone. However, most men lack CTC AR-V7 detection, and additional predictive biomarkers are needed. We conducted a retrospective secondary analysis of the prospective PROPHECY trial (NCT02269982) of men with mCRPC undergoing treatment with enzalutamide/abiraterone, analyzing pooled CTC and germline DNA for whole-genome copy-number alterations (CNA) in 73 samples from 48 men over time along with pooled CTC and germline whole-exome sequencing on 22 paired samples before and following progression on androgen receptor (AR) inhibitor therapy to identify somatic genomic alterations associated with acquired resistance. We observed broad interpatient and longitudinal CTC genomic heterogeneity from AR-V7-negative men with mCRPC, including common gains of KDM6A, MYCN, and AR, and loss of ZFHX3, BRCA1, and PTEN. Men who had progression-free survival of ≤3 months despite enzalutamide/abiraterone treatment were more likely to have baseline CTC genomic loss of CHD1, PTEN, PHLPP1, and ZFHX3 and gains of BRCA2, KDM5D, MYCN, and SPARC. After progression on abiraterone/enzalutamide, we observed clonal evolution of CTCs harboring TP53 mutations and gain of ATM, KDM6A, and MYC, and loss of NCOR1, PTEN, RB1, and RUNX2. CTC genomic findings were independently confirmed in a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (NCT02204943). IMPLICATIONS: We identified common and reproducible genomic alterations in CTCs from AR-V7-negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.

Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer.

Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.

Efficacy and tolerability of current treatments for hormone-refractory prostate cancer patients with visceral metastases.

Aim: To assess the efficacy and tolerability of the first-line treatment options for hormone-refractory prostate cancer patients with visceral metastases. Materials & methods: The records of 191 patients diagnosed with hormone-refractory prostate cancer with visceral metastases were analyzed retrospectively. Results: Docetaxel was administered to 61.2% (n = 117), abiraterone to 14.2% (n = 27) and enzalutamide to 9.4% (n = 18) as the first-line treatment. The median survival of the patients receiving docetaxel, abiraterone and enzalutamide as the first-line treatment during the hormone-refractory period was 15 (95% Cl: 12.9-17) months, 6 (95% Cl: 1.8-10.1) months and 11 (95% Cl: 0.9-23.1) months (p = 0.038), respectively. Conclusion: The present study established a statistically significant difference in favor of docetaxel in terms of overall survival and progression-free survival.

Lay abstract The optimal therapeutic option for castration-resistant prostate cancer (CRPC) patients with visceral metastases is unknown. We assessed the efficacy and tolerability of the first-line treatment options for CRPC patients with visceral metastasis. One hundred ninety-one patients diagnosed with CRPC with visceral metastases were included in the study. The present study established a statistically significant difference in favor of docetaxel in terms of overall survival and progression-free survival between first-line docetaxel, abiraterone and enzalutamide treatments in CRPC patients with visceral metastases. For patients who cannot undergo chemotherapy, enzalutamide, among novel androgen pathway inhibitors, may be the most appropriate option, given its numerical, although statistically insignificant, difference in overall survival and its fewer side effects compared with abiraterone.

Cost-effectiveness analysis of cabazitaxel for metastatic castration resistant prostate cancer after docetaxel and androgen-signaling-targeted inhibitor resistance.

BACKGROUND: The aim of our study was to evaluate the cost-effectiveness of cabazitaxel versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel who had progression within 12 months while receiving an alternative inhibitor (abiraterone or enzalutamide) from a US payer's perspective. METHODS: To conduct the cost-effectiveness analysis, a Markov decision model was established. Three health states (progression-free survival (PFS), progressive disease (PD) and death) were included, and the incremental cost-effectiveness ratio (ICER) was regarded as the primary endpoint. The willingness-to-pay (WTP) threshold was set at $100,000.00/quality-adjusted life year (QALY), and discounted rates were set at 3% annually. Efficacy data were derived from the CARD trial and Weibull distribution curves were modeled to fit the survival curves. The robustness of the analysis was tested with a series of one-way sensitivity analyses and probabilistic sensitivity analyses. RESULTS: Overall, the incremental effectiveness and cost of cabazitaxel versus androgen-signaling-targeted inhibitors (ASTIs) were 0.16 QALYs and $49,487.03, respectively, which yielded an ICER of $309,293.94/QALY. Our model was mostly sensitive to the duration of PFS in the cabazitaxel group, cost of cabazitaxel and utility of the PFS state. At a WTP threshold of $100,000.00/QALY, cabazitaxel was the dominant strategy in 0% of the simulations. CONCLUSIONS: Cabazitaxel is unlikely to be a cost-effective treatment option compared with ASTIs in patients with mCRPC previously treated with docetaxel who had progression within 12 months while receiving ASTIs.

Comparison of effectiveness and safety outcomes of abiraterone versus enzalutamide in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis.

PURPOSE: To compare the effectiveness and safety between abiraterone and enzalutamide in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We systematically searched for relevant articles from PubMed, Cochrane, Embase from their inception through November 4, 2019. Available articles from conferences were searched. The endpoints were prostate-specific antigen (PSA) response, overall survival (OS), progression-free survival (PFS), number of patients with any adverse event (AE). RESULTS: 15 cohort studies involving 3546 participants were included in this meta-analysis. Pooled result showed that PSA response rate in the enzalutamide group was significantly greater than that in the abiraterone group (867 patients, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.61-0.79, p＜0.00001, I2=29%). There was no significant difference in the total incidence of AEs between two groups (730 patients, RR 0.42, 95% CI 0.14-1.31, p = 0.14, I2=84%). The common adverse events observed in the published articles were fatigue and perceived cognitive impairments. Patients who received enzalutamide had the higher risk to have the feeling of fatigue compared with abiraterone group (2555 patients, RR 0.45, 95% CI 0.24-0.85, p=0.01, I2=92%). And there was no statistical difference between two groups respect to the side effect of perceived cognitive impairments (1856 patients, RR 0.94, 95% CI 0.47-1.88, p=0.85, I2=15%). CONCLUSIONS: Our results demonstrated that enzalutamide was associated with higher PSA response rate compared to abiraterone in patients with mCRPC, and no significant difference was found between two groups in the overall AE. But enzalutamide use induced higher risk of the AE of fatigue.

Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime.

BACKGROUND: A new estrogen-free contraceptive has been approved by both the FDA and more than 15 European authorities. It is composed of drospirenone (DRSP) at a dosage of 4 mg in a regimen 24/4. The molecule is known to have anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. The purpose of these clinical trials with a new estrogen-free contraceptive was to introduce a contraceptive method with high efficacy and showing a profile with low cardiovascular risks. METHODS: Three European and American multicenter clinical trials have been conducted in more than 2500 patients and more than 25,000 cycles, not only demonstrating an excellent efficacy (Pearl Index of 0.73) but also investigating possible cardiovascular risks. In the USA study, 422 participants (41.9%) had a risk factor for VTE, while in the European studies, 261 patients (16.6%) had at least one VTE risk factor. Amount of arterial and venous thromboembolic events, hemostasiological data, blood pressure development, and ECG data were evaluated. RESULTS: No single case of VTE was documented, no changes in hemastosiological parameters were observed, a small decrease in RR in patients with pretreatment values between 130 and 140 and/or 85 to 90 mm HG and no influence on ECG parameters were observed. CONCLUSIONS: The introduction of a new estrogen-free contraceptive with 4 mg of non-micronized drospirenone in a 24/4-day regimen expands contraception options for women as not only a high efficacy could be demonstrated during clinical trials but also a very high cardiovascular safety profile was observed even in women with cardiovascular risk factors. TRIAL REGISTRATION: EudraCT registration numbers: 2010-021787-15 & 2011-002396-42 . Clincaltrials.gov: NCT02269241 .

Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters.

OBJECTIVE: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC). STUDY DESIGN: In this randomized, single centre, open-label, exploratory study, healthy women received either 15 mg estetrol/3 mg drospirenone (E4/DRSP) (n = 39), 30 mcg ethinylestradiol/150 mcg levonorgestrel (EE/LNG) (n = 30), or 20 mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (n = 32) for six 28-day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG). RESULTS: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value <0.05 vs E4/DRSP), and +219% for EE/DRSP (p-value <0.05 vs E4/DRSP). Changes to prothrombin fragment 1 + 2 and SHBG for E4/DRSP, EE/LNG, and EE/DRSP were +23%, +71%, and +64% (p-value <0.05 vs E4/DRSP); and +55%, +74% and +251% (p-value <0.05 vs E4/DRSP), respectively. At cycle 6, changes to other hemostasis parameters for E4/DRSP were similar or smaller than for EE/LNG or EE/DRSP. CONCLUSIONS: In this study, changes in hemostasis parameters after treatment with 6 cycles of E4/DRSP were smaller or similar to those observed for EE/LNG. Similar, but more pronounced changes were also observed versus EE/DRSP, which supports the hypothesis that the effect of COCs on hemostasis parameters is mainly mediated by the estrogenic component. Further studies are needed to provide more insight into the venous thromboembolic risk of E4/DRSP. IMPLICATIONS STATEMENT: This study reports that the effects on hemostasis parameters of a COC containing 15 mg E4/3 mg DRSP are less or similar to those for EE/LNG or EE/DRSP. It also demonstrates that the choice of estrogen modulates the effects of COCs on hemostasis parameters.

Adherence and out-of-pocket costs among Medicare beneficiaries who are prescribed oral targeted therapies for advanced prostate cancer.

BACKGROUND: Abiraterone and enzalutamide are high-cost oral therapies that increasingly are used to treat patients with advanced prostate cancer; these agents carry the potential for significant financial consequences to patients. In the current study, the authors investigated coping and material measures of the financial hardship of these therapies among patients with Medicare Part D coverage. METHODS: The authors performed a retrospective cohort study on a 20% sample of Medicare Part D enrollees who underwent treatment with abiraterone or enzalutamide between July 2013 and June 2015. The authors described the variability in adherence rates and out-of-pocket payments among hospital referral regions in the first 6 months of therapy and determined whether adherence and out-of-pocket payments were associated with patient factors and the socioeconomic characteristics of where a patient was treated. RESULTS: There were 4153 patients who filled abiraterone or enzalutamide prescriptions through Medicare Part D in 228 hospital referral regions. The mean adherence rate was 75%. The median monthly out-of-pocket payment for abiraterone and enzalutamide was $706 (range, $0-$3505). After multilevel, multivariable adjustment for patient and regional factors, adherence was found to be lower in patients who were older (69% for patients aged ≥85 years vs 76% for patients aged <70 years; P < .01) and in those with low-income subsidies (69% in those with a subsidy vs 76% in those without a subsidy; P < .01). Both Hispanic ethnicity and living in a hospital referral region with a higher percentage of Hispanic beneficiaries were found to be independently associated with higher out-of-pocket payments for abiraterone and enzalutamide. CONCLUSIONS: There were substantial variations in the adherence rate and out-of-pocket payments among Medicare Part D beneficiaries who were prescribed abiraterone and enzalutamide. Sociodemographic patient and regional factors were found to be associated with both adherence and out-of-pocket payments.